Heterocyclic compounds

ABSTRACT

The present invention relates to novel N-substituted amino alcohols, amino acids and acid derivatives thereof in which a substituted alkyl chain forms part of the N-substituent or salts thereof, to methods for their preparation, to compositions containing them, and to their use for the clinical treatment of painful, hyperalgesic and/or inflammatory conditions in which C-fibers play a pathophysiological role by eliciting neurogenic pain or inflammation.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No. 08/715,665filed Sep. 18, 1996 and claims priority under 35 U.S.C. 119 of Danishapplication Ser. Nos. 1040/95 and 1041/95 filed Sep. 19, 1995, thecontents of which are fully incorporated herein by reference, now U.S.Pat. No. 5,753,678.

FIELD OF THE INVENTION

The present invention relates to novel N-substituted amino alcohols,amino acids and acid derivatives thereof in which a substituted alkylchain forms part of the N-substituent or salts thereof, to methods fortheir preparation, to compositions containing them, and to their use forthe clinical treatment of painful, hyperalgesic and/or inflammatoryconditions in which C-fibers play a pathophysiological role by elicitingneurogenic pain or inflammation.

The invention also relates to the use of the present compounds for thetreatment of insulin resistance in non-insulin-dependent diabetesmellitus (NIDDM) or ageing, the present compounds knowing to interferewith neuropeptide containing C-fibres and hence inhibit the secretionand circulation of insulin antagonizing peptides like CGRP or amylin.

BACKGROUND OF THE INVENTION

The nervous system exerts a profound effect on the inflammatoryresponse. Antidromic stimulation of sensory nerves results in localizedvasodilation and increased vascular permeability (Janecso et al. Br. J.Pharmacol. 1967, 31, 138-151) and a similar response is observedfollowing injection of peptides known to be present in sensory nerves.From this and other data it is postulated that peptides released fromsensory nerve endings mediate many inflammatory responses in tissueslike skin, joint, urinary tract, eye, meninges, gastro-intestinal andrespiratory tracts. Hence inhibition of sensory nerve peptide releaseand/or activity, may be useful in treatment of, for example arthritis,dermatitis, rhinitis, asthma, cystitis, gingivitis, thrombo-phlebitis,glaucoma, gastro-intestinal diseases or migraine.

Further, the potent effects of CGRP on skeletal muscle glycogen synthaseactivity and muscle glucose metabolism, together with the notion thatthis peptide is released from the neuromuscular junction by nerveexcitation, suggest that CGRP may play a physiological role in skeletalmuscle glucose metabolism by directing the phosphorylated glucose awayfrom glycogen storage and into the glycolytic and oxidative pathways(Rossetti et al. Am. J. Physiol. 264, E1-E10, 1993). This peptide mayrepresent an important physiological modulator of intracellular glucosetrafficking in physiological conditions, such as exercise, and may alsocontribute to the decreased insulin action and skeletal muscle glycogensynthase in pathophysiological conditions like NIDDM orageing-associated obesity (Melnyk et al. Obesity Res. 3, 337-344, 1995)where circulating plasma levels of CGRP are markedly increased. Henceinhibition of release and/or activity of the neuropeptide CGRP may beuseful in the treatment of insulin resistance related to type 2 diabetesor ageing.

In U.S. Pat. No. 4,383,999 and U.S. Pat. No. 4,514,414 and in EP 236342as well as in EP 231996 some derivatives ofN-(4,4-disubstituted-3-butenyl)azaheterocyclic carboxylic acids areclaimed as inhibitors of GABA uptake. In EP 342635 and EP 374801,N-substituted azaheterocyclic carboxylic acids in which an oxime ethergroup and vinyl ether group forms part of the N-substituent respectivelyare claimed as inhibitors of GABA uptake. Further, in WO 9107389 and WO9220658, N-substituted azacyclic carboxylic acids are claimed as GABAuptake inhibitors. EP 221572 claims that1-aryloxyalkylpyridine-3-carboxylic acids are inhibitors of GABA uptake.

In DE 2833892 some 12H-dibenzo[d,g][1,3,6]dioxozocine derivatives areclaimed as local anaesthetics or for treatment of parkinsonism.

DESCRIPTION OF THE INVENTION

The present invention relates to novel N-substituted amino alcohols,amino acids and acid derivatives thereof of formula I ##STR1## whereinR¹ and R² independently are hydrogen, halogen, trifiuoromethyl, hydroxy,

C₁₋₆ -alkyl or C₁₋₆ -alkoxy; and

R³ is hydrogen or C₁₋₃ -alkyl; and

A is C₁₋₃ -alkylene; and

Y is>CH--CH₂ --, >C═CH--, >CH--O--, >C═N--, >N--CH₂ -- wherein only theunderscored atom participates in the ring system; and

Z is selected from ##STR2## wherein n is 1 or 2; and R¹¹ is hydrogen orC₁₋₆ -alkyl; and

R¹² is hydrogen, C₁₋₆ -alkyl, C₁₋₆ -alkoxy or phenyl optionallysubstituted with halogen, trifluoromethyl, hydroxy, C₁₋₆ -alkyl or C₁₋₆-alkoxy; and

R¹³ is hydrogen, halogen, trifluoromethyl, hydroxy, C₁₋₆ -alkyl or C₁₋₆alkoxy; and

R¹⁴ is --(CH₂)_(m) OH or --(CH₂)_(t) COR¹⁵ wherein m is 0, 1, 2, 3, 4, 5or 6 and t is 0 or 1 and

wherein R¹⁵ is --OH, NH₂, --NHOH or C₁₋₆ -alkoxy; and

R¹⁶ is C₁₋₆ -alkyl or --B--COR¹⁵, wherein B is C₁₋₆ -alkylene, C₂₋₆-alkenylene or C₂₋₆ -alkynylene and

R¹⁵ is the same as above; and

. . is optionally a single bond or a double bond;

or a pharmaceutically acceptable salt thereof.

The compounds of formula I may exist as geometric and optical isomersand all isomers and mixtures thereof are included herein. Isomers may beseparated by means of standard methods such as chromatographictechniques or fractional crystallisation of suitable salts.

Preferably, the compounds of formula I exist as the individual geometricor optical isomers.

The compounds according to the invention may optionally exist aspharmaceutically acceptable acid addition salts or--when the carboxylicacid group is not esterified--as pharmaceutically acceptable metal saltsor--optionally alkylated--ammonium salts.

Examples of such salts include inorganic and organic acid addition saltssuch as hydrochloride, hydrobromide, sulphate, phosphate, acetate,fumarate, maleate, citrate, lactate, tartate, oxalate or similarpharmaceutically acceptable inorganic or organic acid addition salts,and include the pharmaceutically acceptable salts listed in Journal ofPharmaceutical Science, 66, 2 (1977) which are hereby incorporated byreference.

The term "C₁₋₆ -alkyl" as used herein, alone or in combination, refersto a straight or branched, saturated hydrocarbon chain having 1 to 6carbon atoms such as e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl,n-hexyl, 4-methylpentyl, neopentyl, n-hexyl, 1,2-dimethylpropyl,2,2-dimethylpropyl and 1,2,2-trimethylpropyl.

The term "C₁₋₆ -alkoxy" as used herein, alone or in combination, refersto a straight or branched monovalent substituent comprising a C₁₋₆-alkyl group linked through an ether oxygen having its free valence bondfrom the ether oxygen and having 1 to 6 carbon atoms e.g. methoxy,ethoxy, propoxy, isopropoxy, butoxy, pentoxy.

The term "halogen" means fluorine, chlorine, bromine or iodine.

Illustrative examples of compounds encompassed by the present inventioninclude:

2-Chloro-12-(3-dimethylamino)propylidene-12H-dibenzo[d,g][1,3]dioxocine

2,10-Dichloro-12-(2-dimethylamino)ethoxy-12H-dibenzo[d,g][1,3]dioxocine.

2,10-Dichloro-12-(3-dimethylamino)propyl-12H-dibenzo[d,g][1,3]dioxocine

2,10-Dichloro-12-(3-dimethylamino-1-methyl)ethoxy-12H-dibenzo[d,g][1,3]dioxocine

3-Chloro-12-(2-dimethylaminopropylidene)-12H-dibenzo[d,g][1,3]dioxocine

3-Chloro-12-(3-dimethylamino)propylidene-12H-dibenzo[d,g][1,3]-dioxocine

3-Chloro-12-(3-dimethylamino-1-methylpropylidene)-12Hdibenzo-[d,g][1,3]-dioxocine

2-Fluoro-12-(3-dimethylamino)propylidene-12H-dibenzo[d,g][1,3]dioxocine

2-Methyl-12-(3-(4-methyl-1-piperazinyl)propylidene)-12H-dibenzo[d,g][1,3]dioxocine

2-Chloro-12-(3-(4-methyl-1-piperazinyl)propylidene)-12H-dibenzo[d,g][1,3]dioxocine

3-Chloro-12-(3-(4-methyl-1-piperazinyl)propylidene)-12H-dibenzo[d,g][1,3]-dioxocine

1-(3-(12H-Dibenzo[d,g][1,3]dioxocin-12-ylidene)propyl)-3-piperidinecarboxylicacid ethylester

1-(3-(12H-Dibenzo[d,g][1,3]dioxocin-12-ylidene)propyl)-3-piperidinecarboxylicacid

or a pharmaceutically acceptable salt thereof.

As used herein, the term "patient" includes any mammal which couldbenefit from treatment of neurogenic pain or inflammation or insulinresistance in NIDDM. The term particularly refers to a human patient,but is not intended to be so limited.

It has been demonstrated that the novel compounds of formula I inhibitneurogenic inflammation which involves the release of neuropeptides fromperipheral and central endings of sensory C-fibres. Experimentally thiscan be demonstrated in animal models of formalin induced pain or pawoedema (Wheeler and Cowan, Agents Actions 1991, 34, 264-269) in whichthe novel compounds of formula I exhibit a potent inhibitory effect.Compounds of formula I may be used to treat all painful, hyperalgesicand/or inflammatory conditions in which C-fibers play apathophysiological role by eliciting neurogenic pain or inflammation,i.e.:

Acutely painful conditions exemplified by migraine, postoperative pain,burns, bruises, post-herpetic pain (Zoster) and pain as it is generallyassociated with acute inflammation; chronic, painful and/or inflammatoryconditions exemplified by various types of neuropathy (diabetic,post-traumatic, toxic), neuralgia, rheumatoid arthritis, spondylitis,gout, inflammatory bowel disease, prostatitis, cancer pain, chronicheadache, coughing, asthma, chronic pancreatitis, inflammatory slindisease including psoriasis and autoimmune dermnatoses, osteoporoticpain.

Further, it has been demonstrated that the compounds of general formulaI improves the glucose tolerance in diabetic ob/ob mice and that thismay result from the reduced release of CGRP from peripheral nervousendings. Hence the compounds of general formula I may be used in thetreatment of NIDDM as well as ageing-associated obesity. Experimentallythis has been demonstrated by the subcutaneous administration of glucoseinto ob/ob mice with or without previous oral treatment with a compoundof general formula I.

The compounds of formula I may be prepared by the following method:##STR3##

A compound of formula II wherein R¹, R², R³, A, and Y are as definedabove and W is a suitable leaving group such as halogen, p-toluenesulphonate or mesylate may be reacted with an azaheterocyclic compoundof formula III wherein Z is as defined above. This alkylation reactionmay be carried out in a solvent such as acetone, dibutylether,2-butanone, methyl ethyl ketone, ethyl acetate, tetrahydrofulan (THF) ortoluene in the presence of a base e.g. sodium hydride and a catalyst,e.g. an alkali metal iodide at a temperature up to reflux temperaturefor the solvent used for e.g. 1 to 120 h. If esters have been preparedin which R¹⁵ is alkoxy, compounds of formula I wherein R¹⁵ is OH may beprepared by hydrolysis of the ester group, preferably at roomtemperature in a mixture of an aqueous alkali metal hydroxide solutionand an alcohol such as methanol or ethanol, for example, for about 0.5to 6 h.

Compounds of formula II and III may readily be prepared by methodsfamiliar to those skilled in the art.

Under certain circumstances it may be necessary to protect theintermediates used in the above methods e.g. a compound of formula IIIwith suitable protecting groups. The carboxylic acid group can, forexample, be esterified. Introduction and removal of such groups isdescribed in "Protective Groups in Organic Chemistry" J. F. W. McOrnieed. (New York, 1973).

Pharmacological Methods

I. Formalin Induced Pain or Paw Oedema

Values for in vivo inhibition of formalin induced pain or oedema for thecompounds of the present invention were assessed in mice essentially bythe method of Wheeler-Aceto and Cowan (Agents Action 1991, 34, 265-269).

About 20 g NMRI female mice were injected 20 ml 1% formalin into theleft hind paw. The animals were then placed on a heated (31° C.) table,and the pain response was scored. After 1 h they were killed and bled.Left and right hind paws were removed and the weight difference betweenthe paws was used as indication of the oedema response of the formalininjected paw.

II. Histamin Induced Paw Oedema

Values for in vivo inhibition of histamine induced oedema for thecompounds of the present invention were assessed in rats essentially asdescribed by Amann et al. (Europ. J. Pharmacol. 279, 227-231, 1995).

In brief 250-300 g male Sprague-Dawley rats were anaesthetized withpentobarbital sodium, and placed on a 32 degree heated table. Tenminutes later histamine (50 microliter, 3 mg/ml) was injected in theright hind paw and 20 minutes hereafter the paw swelling was determinedby water plethysmography (Ugo Basile). Test compounds were administeredintraperitoneally at 15 minutes before the anaesthetics.

                  TABLE 1                                                         ______________________________________                                        Inhibition of histamine induced oedema at 1 mg/kg                                    Example no.                                                                              %oedema inhibition                                          ______________________________________                                        2            52                                                                 3            33                                                             ______________________________________                                    

III. Reduced Release of CGRP

ob/ob female mice, 16 weeks of age, where injected glucose (2 g/kg)subcutaneously. At times hereafter blood glucose was determined in tailvenous blood by the glucose oxidase method. At the end of the study theanimals were decapitated and trunk blood collected. Immunoreactive CGRPwas determined in plasma by radio-immuno-assay. Two groups of animalswere used. The one group was vehicle treated, whereas the other groupreceived a compound of formula I via drinking water (100 mg/l) for fivedays before the test.

For the above indications the dosage will vary depending on the compoundof formula I employed, on the mode of administration and on the therapydesired. However, in general, satisfactory results are obtained with adosage of from about 0.5 mg to about 1000 mg, preferably from about 1 mgto about 500 mg of compounds of formula I, conveniently given from 1 to5 times daily, optionally in sustained release form. Usually, dosageforms suitable for oral administration comprise from about 0.5 mg toabout 1000 mg, preferably from about 1 mg to about 500 mg of thecompounds of formula I admixed with a pharmaceutical carrier or diluent.

The compounds of formula I may be administered in a pharmaceuticallyacceptable acid addition salt form or where possible as a metal or alower alkylammonium salt. Such salt forms exhibit approximately the sameorder of activity as the free base forms.

This invention also relates to pharmaceutical compositions comprising acompound of formula I or a pharmaceutically acceptable salt thereof and,usually, such compositions also contain a pharmaceutical carrier ordiluent. The compositions containing the compounds of this invention maybe prepared by conventional techniques and appear in conventional forms,for example capsules, tablets, solutions or suspensions.

The pharmaceutical carrier employed may be a conventional solid orliquid carrier. Examples of solid carriers are lactose, terra alba,sucrose, talc, gelatine, agar, pectin, acacia, magnesium stearate andstearic acid. Examples of liquid carriers are syrup, peanut oil, oliveoil and water.

Similarly, the carrier or diluent may include any time delay materialknown to the art, such as glyceryl monostearate or glyceryl distearate,alone or mixed with a wax.

If a solid carrier for oral administration is used, the preparation canbe tabletted, placed in a hard gelatine capsule in powder or pellet formor it can be in the form of a troche or lozenge. The amount of solidcarrier will vary widely but will usually be from about 25 mg to about 1g. If a liquid carrier is used, the preparation may be in the form of asyrup, emulsion, soft gelatine capsule or sterile injectable liquid suchas an aqueous or non-aqueous liquid suspension or solution.

Generally, the compounds of this invention are dispensed in unit dosageform comprising 50-200 mg of active ingredient in or together with apharmaceutically acceptable carrier per unit dosage.

The dosage of the compounds according to this invention is 1-500 mg/day,e.g. about 100 mg per dose, when administered to patients, e.g. humans,as a drug.

A typical tablet which may be prepared by conventional tablettingtechniques contains

    ______________________________________                                        Core:                                                                           Active compound (as free compound          100 mg                             or salt thereof)                                                              Colloidal silicon dioxide (Aerosil*)        1.5 mg                            Cellulose, microcryst. (Avicel*)            70 mg                             Modified cellulose gum (Ac-Di-Sol*)         7.5 mg                            Magnesium stearate                                                            Coating:                                                                      HPMC                         approx. 9 mg                                     •Mywacett* 9-40 T     approx. 0.9 mg                                  ______________________________________                                         •Acylated monoglyceride used as plasticizer for film coating.      

The route of administration may be any route which effectivelytransports the active compound to the appropriate or desired site ofaction, such as oral or parenteral e.g. rectal, transdermal,subcutaneous, intanasal, intramuscular, topical, intravenous,intraurethrai, ophthalmic solution or an ointment, the oral route beingpreferred.

EXAMPLES

The process for preparing compounds of formula I and preparationscontaining them is further illustrated in the following examples, which,however, are not to be construed as limiting.

Hereinafter, TLC is thin layer chromatography and CDCl₃ is deuteriochloroform and DMSO-d₆ is hexadeuterio dimethylsulfoxide. The structuresof the compounds are confirmed by either elemental analysis or NMR,where peaks assigned to characteristic protons in the title compoundsare presented where appropriate. ¹ H-NMR shifts (δ_(H)) are given inparts per million (PPM). M.p. is melting point and is given in ° C. andis not corrected. Column chromatography was carried out using thetechnique described by W. C. Still et al, J. Org. Chem. (1978), 43,2923-2925 on Merck silica gel 60 (Art. 9385). Compounds used as startingmaterials are either known compounds or compounds which can readily beprepared by methods known per se.

Example 1

1-(3-(12H-Dibenzo[d,g][1,3]dioxocin-12-ylidene)-1-propyl)-3-piperidinecarboxylicacid hydrochloride ##STR4##

2,2'-Dihydroxybenzophenone (10.0 g, 46.7 mmol) and diiodomethane (13.1g, 49 mmol) was dissolved in dry dimethylformamide (180 ml). Dried,finely powdered potassium carbonate (9.2 g, 66.7 mmol) was added, andthe mixture was heated at 105° C. for 16 h. After cooling to roomtemperature the reaction mixture was poured into ice water (500 ml). Theprecipitate was collected by filtration after 0.5 h, washed with wateron the filter and dissolved in a mixture of ethanol (80 ml) and 4 Nsodium hydroxide (20 ml). The solution was stirred at reflux temperaturefor 1 h, cooled and diluted with water (300 ml). The formed crystallineprecipitate was filtered off, washed with water (50 ml) and dried invacuo, affording 12H-dibenzo[d,g][1,3]dioxocin-2-one as a solid (9.5 g,90% yield).

M.p. 93-95° C.

A solution of cyclopropylmagnesium bromide in dry tetrahydrofuran(prepared from cyclopropylbromide (24.2 g, 0.2 mol), magnesium turnings(4.86 g, 0.2 mol) and dry tetrahydrofuran (70 ml) was placed under anatmosphere of nitrogen. A solution of the above ketone (9.05 g, 40 mmol)in dry tetrahydrofuran (50 ml) was added dropwise. The reaction mixturewas stirred at 40° C. for 1.5 h, cooled and added to an ice-cold mixtureof saturated ammonium chloride (400 ml) and ether (200 ml). The organiclayer was separated, the aqueous phase was extracted with ether (50 ml),the combined organic extracts were washed with water (2×100 ml) andbrine (50 ml), dried over MgSO₄, evaporated in vacuo and stripped withtoluene (2×25 ml) to furnish 11.2 g12-cyclopropyl-12H-dibenzo[d,g][1,3]dioxocin-12-ol.

¹ H NMR (200 MHz, CDCl₃): δ 0.50 (d, 2H); 0.75 (d, 2H); 2.00 (m, 1H);5.14 (s, 2H); 6.9-7.4 (m, 6H); 7.81 (d, 2H).

To a solution of the above alcohol (6.21 g, 22 mmol) in drydichloromethane (225 ml) trimethylsilylbromosilane (3.71 g, 24.2 mmol)was added. The reaction mixture was stirred at room temperature for 1 hand poured on an ice-cold saturated sodium hydrogencarbonate solution(75 ml). The organic phase was separated, washed with icewater (2×75 ml)and brine (75 ml), dried over MgSO₄ and evaporated in vacuo, whichafforded 7.95 g of crude12-(3-bromo-1-propylidene)-12H-dibenzo[d,g][1,3]dioxocine, which wasused in the next step without further purification.

A mixture of the above crude bromide (1.83 g, 5.5 mmol), ethyl3-piperidinecarboxylate (0.865 g, 5.5 mmol), dried potassium carbonate(2.28 g, 16.5 mmol), sodium iodide (0.82 g, 5.5 mmol) and 2-butanone (25ml) was heated at reflux temperature for 3 h. After cooling to roomtemperature, diethyl ether (50 ml) and water (50 ml) was added to thereaction mixture. The organic layer was separated, washed with water(2×50 ml) and made acidic by addition of 2 N hydrochloric acid. Theaqueous layer was separated and the organic phase was extracted twicewith water (50 ml). The combined aqueous extracts were adjusted to pH8.5 with a saturated sodium bicarbonate solution and extracted withdichloromethane (2×25 ml). The organic extract was washed with water (50ml) dried over MgSO₄ and evaporated in vacuo, which afforded1-(3-(12H-dibenzo[d,g][1,3]dioxocin-12-ylidene)-1-propyl)-3-piperidinecarboxylicacid ethyl ester as a foam (1.66 g, 74%).

The above ester (1.66 g, 4.0 mmol) was dissolved in ethanol (20 ml) and2 N sodium hydroxide (6.6 ml, 13.2 mmol) was added. The mixture wasstirred at room temperature for 1.5 h. The ethanol was evaporated invacuo and the remainder was diluted with water (25 ml). 1 N Hydrochloricacid (17.6 ml) was added and the solution was washed with diethyl ether(25 ml). The aqueous phase was extracted with dichloromethane (3×30 ml).The combined organic extracts were dried over MgSO₄ and evaporated invacuo to afford 1.1 g of the title compound as a foam, which wastriturated with ethyl acetate, filtered off and dried.

M.p. 190-92° C., decomp.

Calculated for C₂₃ H₂ NO₄, HCl 0.25 C₄ H₈ O₂ : C, 65.82%; H, 6.44%; N,3.20%; Found: C, 65.76%; H, 6.58%; N, 3.05%.

Example 2

(R)-1-(3-(12H-Dibenzo[d,g][1,3]dioxocin-12-ylidene)-1-propyl)-3-piperidinecarboxylicacid hydrochloride ##STR5##

A mixture of 12-(3-bromo-1-propyhdene)12H-dibenzo[d,g,][1,3]dioxocine(7.90 g, 22 mmol, prepared as described in example 1,(R)-3-piperidinecarboxylic acid ethyl ester (L)-tartrate (6.60 g, 22mmol), dry potassium carbonate (12.2 g, 88 mmol), sodium iodide (3.5 g,22 mmol) and 2-butanone (100 ml) was heated at reflux temperature for 16h. After cooling to room temperature, diethyl ether (100 ml) and water(100 ml) was added. The organic layer was separated, washed with water(2×50 ml) and made acidic by addition of 2 N hydrochloric acid. Theaqueous layer was separated and the organic phase was extracted twicewith water (50 ml).

The combined aqueous extracts were adjusted to pH 8.5 with a saturatedsodium bicarbonate solution and extracted with dichloromethane (2×25ml). The organic extract was washed with water (50 ml) dried over MgSO₄and evaporated in vacuo. The resulting residue (6.21 g) was purified bychromatography on silica gel using a mixture of toluene and ethylacetate as eluent to give(R)-1-(3-(12H-dibenzo[d,g][1,3]dioxocin-12-ylidene)-1-propyl)-3-piperidinecarboxylicacid ethyl ester as an oil (3.96 g, 41%).

The above ester (3.06 g, 7.5 mmol) was dissolved in ethanol (40 ml) and2 N sodium hydroxide (12.4 ml, 24.8 mmol) was added. The mixture wasstirred at room temperature for 1.0 h. The ethanol was evaporated invacuo and the remainder was diluted with water (25 ml). The pH wasadjusted to 6 by addition of 1 N hydrochloric acid and the solution waswashed with diethyl ether (25 ml). The aqueous phase was extracted withdichloromethane (3×30 ml). The combined organic extracts were dried overMgSO₄ and evaporated in vacuo to afford 2.75 g of a foam, which wasdissolved in tetrahydrofuran (75 ml). Dropwise addition of excesshydrogen chloride in ether afforded the title compound as crystals,which were filtered off and dried (2.65 g, 85%).

M.p. 227-228° C., decomp.

Calculated for C₂₃ H₂₅ NO₄, HCl: C, 66.42%; H, 6.30%; N, 3.37%; Found:C, 66.50%; H, 6.61%; N, 3.14%.

EXAMPLE 3

(R)-1-(3-(12H-Dibenzo[d,g][1,3]dioxocin-12-ylidene)-1-propyl)-3-piperidinecarboxylicacid ethyl ester hydrochloride

(R)-1-(3-(12H-dibenzo[d,g][1,3]dioxocin-12-ylidene)-1-propyl)-3-piperidinecarboxylicacid ethyl ester (0.86 g, 2.1 mmol, prepared as described in example 2was dissolved in tetrahydrofuran (10 ml) and a 2.6 N solution ofhydrogen chloride in ether (0.97 ml, 2.52 mmol) was added dropwise. Thesolution was evaporated in vacuo and the remainder was treated withether (20 ml). The precipitate was filtered off, washed with ether anddried in vacuo, affording the title compound as a powder.

Calculated for C₂₅ H₂₉ NO₄, HCl, 0.5 H₂ O: C, 66.29%; H, 6.90%; N,3.09%; Found: C, 65.97%; H, 7.03%; N, 2.87%.

EXAMPLE 4

1-(3-(12H-Dibenzo[d,g][1,3]dioxocin-12-ylidene)-1-propyl)-4-piperidinecarboxylicacid hydrochloride ##STR6##

A mixture of 12-(3-bromo-1-propylidene)-12H-dibenzo[d,g][1,3]dioxocine(4.0 g, 12 mmol, prepared as described in example 1,4-piperidinecarboxylic acid ethyl ester (1.9 g, 12 mmol), anhydrouspotassium carbonate (5.0 g) and sodium iodide (0.2 g) inN,N-dimethylformamide (40 ml) was heated at 60-70° C. for 5 h. Aftercooling, the inorganic salts were filtered off and washed with benzene(40 ml), and the filtrate was diluted with additional benzene (120 ml).The benzene solution was washed with water (3×50 ml), dried over MgSO₄and evaporated in vacuo. The oily residue (4.8 g) was purified bychromatography on silica gel using a mixture of benzene and ethylacetate as eluent to give1-(3-(12H-dibenzo[d,g][1,3]dioxocin-12-ylidene)-1-propyl)-4-piperidinecarboxylicacid ethyl ester as an oil (2.3 g, 47%).

The above ester (2.30 g, 5.6 mmol) was dissolved in ethanol (30 ml), a20% solution of sodium hydroxide (3.5 ml) was added and the mixture wasstirred at room temperature for 7 h. The solution was diluted withdichloromethane (240 ml) and acidified with concentrated hydrochloricacid (3 ml). The mixture was washed with water (10 ml), the organicphase was dried over MgSO₄ and evaporated in vacuo. The solid residuewas washed with acetone, filtered off and dried in vacuo, affording thetitle compound (1.8 g, 73%).

M.p. 239-245° C.

Calculated for C₂₃ H₂₅ NO₄, HCl, 0.5 C₂ H₅ OH: C, 65.67%; H, 6.66%; Cl,8.08%; N, 3.19%; Found: C, 65.51%; H, 6.35%; Cl, 8.78%; N, 3.27%.

EXAMPLE 5

(R)-1-(3-(2,10-Dichloro-12H-dibenzo[d,g][1,3]-dioxocin-12-ylidene)-1-propyl)-3-piperidinecarboxylicacid hydrochloride ##STR7##

2,2'-Dihydroxy-5,5'-dichlorobenzophenone (12.1 g, 0.042 mol, preparedsimilarly as described in Journal of the American Chemical Society 77,543 (1955)) and diiodomethane (11.9 g, 0.044 mol) were dissolved in dryN,N-dimethylformamnide (226 ml). Dried and powdered potassium carbonate(8.3 g) was added and the mixture was heated at 105° C. for 5 h and leftovernight at room temperature. The reaction mixture was poured on ice(220 g). The precipitate was collected by filtration after 0.5 h anddissolved in diethyl ether (500 ml). The organic layer was washed with5% sodium hydroxide (50 ml), dried over MgSO₄ and evaporated in vacuo,affording 12 g (96%) of2,10-dichloro-12H-dibenzo[d,g][1,3]-dioxocin-12-one as a solid.

To a solution of cyclopropylmagnesium bromide in dry tetrahydrofuran(prepared from cyclopropylbromide (15.7 g, 0.130 mol), magnesiumturnings (3.15 g, 0.130 mol) and dry tetrahydrofuran (45 ml)), asolution of the above ketone (7.65 g, 0.026 mol) in dry tetrahydrofuran(30 ml) was added over 5 minutes with cooling. The reaction mixture wasstirred at 38-42° C. for 3 h, cooled in an ice-bath, and a mixture ofsaturated ammonium chloride (260 ml) and diethyl ether (130 ml) wasadded. The reaction mixture was filtered, the organic layer wasseparated, the aqueous phase was extracted with diethyl ether (35 ml).The combined organic extracts were washed with water (2×70 ml) and brine(70 ml), dried over MgSO₄ and evaporated in vacuo. The crude product waspurified by column chromatography on silica gel (140 g) using benzene aseluent. This afforded 8.75 g (98%) of2,10-dichloro-12-cyclopropyl-12H-dibenzo[d,g][1,3]dioxocin-12-ol as asolid. To a solution of the above alcohol (8.75 g, 0.027 mol) in drydichloromethane (245 ml) trimethylsilyl bromide (4.02 g, 0.026 mol) wasadded. The reaction mixture was stirred at room temperature for 1 h andpoured on an ice cold saturated sodium hydrogencarbonate solution (80ml). The organic phase was separated, washed with water (2×80 ml) andbrine (80 ml), dried over MgSO₄ and evaporated in vacuo. This afforded9.12 g of an oil, which was purified by column chromatography on silicagel (250 g) using a mixture of cyclohexane and benzene (3:1) as eluent.This yielded 6.61 g (61.8%) of2,10-dichloro-12-(3-bromo-1-propylidene)-12H-dibenzo[d,g][1,3]-dioxocineas an oil which crystallized on standing.

A mixture of the above bromide (3.0 g, 0.0075 mol),(R)-3-piperidinecarboxylic acid ethyl ester tartrate (3.45 g, 0.0112mol), dried potassium carbonate (10.35 g, 0.075 mol) anddimethylformamide (42 ml) was heated at 60° C. for 12 h. After coolingto room temperature, water (150 ml) and benzene (75 ml) were added. Theorganic layer was separated, washed with water (3×60 ml), dried overMgSO₄ and evaporated in vacuo. The crude oil was purified by columnchromatography on silica gel (65 g) using chloroform as eluent. Thisafforded 1.44 g (40%) of (R)-1-(3-(2,10-dichloro-12H-dibenzo[d,g][1,3]-dioxocin-12-ylidene)-1-propyl)-3-piperidinecarboxylic acidethyl ester as an oil.

The above ester (1.44 g, 0.003 mol) was dissolved in ethanol (25 ml) and4 N sodium hydroxide (3.36 ml, 0.013 mol) was added. The mixture wasleft at room temperature overnight. Concentrated hydrochloric acid (1.68ml), followed by dichloromethane (170 ml) were added, the organic layerwas separated, dried over MgSO₄ and evaporated. Evaporation was repeatedwith dichloromethane (120 ml) and acetone (20 ml). The oily residue wasdissolved in acetone (10 ml), yielding, after 12 h at room temperature,0.54 g (37%) of the title compound as crystals.

¹ H NMR (250 MHz, DMSO-d₆, δ_(H)): 7.49 (d, J=2.5 Hz, 1 H); 7.32 (dd,J=2.5 Hz and 8.8 Hz, 1 H);7.26 (dd, J=2.5 Hz and 8.8 Hz, 1 H); 7.19 (d,J=2.5 Hz, 1 H); 7.09 (d, J=8.8 Hz, 1 H); 6.97 (d, J=8.8 Hz, 1 H); 6.09(t, J=7.2 Hz, 1 H); 5.84 (s, 2 H); 2.43 (q, J=7.2 Hz, 2 H); 3.15 (t,J=7.2 Hz).

Calculated for C₂₃ H₂₃ Cl₂ NO₂, HCl, 0.5 C₃ H₆ O: C, 57.26%; H, 5.30%;N, 2.73%; Cl, 20.70%; Found: C, 56.95%; H, 5.31%; N, 2.53%; Cl, 20.75%.

EXAMPLE 6

1-(3-(12H-Dibenzo[d,g][1,3]dioxocin-12-ylidene)-1-propyl)-3-pyrrolidineaceticacid hydrochloride ##STR8##

A mixture of 12-(3-bromo-1-propylidene)-12H-dibenzo[d,g][1,3]dioxocine(5.00 g, 15 mmol, prepared as described in example 1, methyl3-pyrrolidineacetate acetate (3.04 g, 15 mmol), potassium carbonate (6.2g, 45 mmol) and potassium iodide (2.23 g, 13 mmol) in 2-butanone (70 ml)was heated at reflux temperature for 5 h. The reaction mixture wascooled and water (140 ml) and ether (140 ml) were added. The mixture wasvigorously stirred for 5 minutes, the organic layer was separated,washed with water (2×50 ml) and dried over MgSO₄. The solvent wasevaporated in vacuo and the residue (4.34 g) was submitted to columnchromatography on silica gel (100 g) using a mixture of dichloro-methane and methanol (10:1) as eluent. This afforded 1.05 g of1-(3-(12H-dibenzo[d,g][1,3]dioxocin-12-ylidene)-1-propyl)-3-pyrrolidineaceticacid methyl ester.

To a solution of the above ester (0.85 g, 2.1 mmol) in ethanol (16 ml),20% sodium hydroxide (1.3 ml) was added, the mixture was stirred at roomtemperature for 2 h and left to stand overnight. The solution was pouredinto dichloromethane (100 ml), cooled in an ice bath, acidified with 2 Nhydrochloric acid and stirred for 10 minutes. Additional water was added(5 ml). The organic layer was dried over MgSO₄, partially decolorizedwith active charcoal and evaporated in vacuo. The hydrochloride of thetitle compound separated as an amorphous hygroscopic solid (0.64 g,77%).

M.p. 70-90° C.

¹ H NMR (250 MHz, CDCl₃ )δ_(H) : 7.15 (m, ˜8 H); 5.95 (t, J=7.2 Hz, 1H);5.85 (s, 2 H) 3.36-1.51 (bm, 13H).

Calculated for C₂₃ H₅ NO₄, HCl, 0.5 C₂ H₆ O. C, 65.67%; H, 6.66%; N,3.19%; Found: C, 65.79%; H, 6.59%; N, 3.21%.

EXAMPLE 7

1-(3-(2,10-Dichloro-2H-dibenzo[d,g][1,3]dioxocin-12-ylidene)-1-propyl)-3-pyrrolidineacetic acidhydrochloride ##STR9##

A mixture of2,10-dichloro-12-(3-bromo-1-propylidene)-12H-dibenzo[d,g][1,3]-dioxocine(4.0 g, 0.01 mol, prepared as described in example 4, 3-pyrrolidinaceticacid methyl ester acetate (2.23 g, 0.011 mol), potassium carbonate (4.5g, 0.0325 mol) and sodium iodide (1.1 g, 7.3 mmol) in 2-butanone (60 ml)was heated at reflux temperature for 6 h. After cooling to roomtemperature the reaction mixture was diluted with acetone, filtered andevaporated in vacuo. The crude product was purified by columnchromatography on silica gel (200 g), using a mixture of chloroform(95%) and ethanol (5%) as eluent. This afforded 0. 8 g (17.3%) of1-(3-(2,10-dichloro-12H-dibenzo[d,g][1,3]dioxocin-12-ylidene)-1-propyl-3-pyrrolidineaceticacid methyl ester as an oil.

To the above ester (0.8 g, 1.78 mmol) in ethanol (11.6 ml) a solution ofsodium hydroxide (0.288 g) in water (1.08 ml) was added and the reactionmixture was stirred at room temperature for 16 h. Concentratedhydrochloric acid (1.08 ml) was added followed by dichloromethane (80ml). After stirring for 10 minutes the organic layer was separated,dried over MgSO₄ and evaporated in vacuo. The residue was dissolved inacetone (20 ml) and evaporated. The re-evaporation with acetone wasrepeated twice. The residue was again dissolved in acetone (40 ml) andleft at 0° C. for 4 h. This afforded 300 mg (36%) of the title compoundas a solid.

M.p. 183-193° C., decomp.

Calculated for CH,CI₂ NO₄, HCl: C, 56.98%; H, 4.99%; N, 2.89%; Found: C,56.92%; H,5.02%; N, 3.16%.

EXAMPLE 8

(R)-1-(2-(12H-Dibenzo[d,g][1,3]dioxocin-12-yloxy)-1-ethyl)-3-piperidinecarboxylicacid acetate ##STR10##

To a suspension of 12H-dibenzo[d,g][1,3]dioxocin-12-one (9.05 g, 40mmol) in ethanol (140 ml) a solution of sodium borohydride (0.8 g, 21mmol) in water (5 ml containing 2 drops of 10% sodium hydroxide) wasadded dropwise at 40° C. and the reaction mixture was stirred at 70° C.for 5 h. Additional solid sodium borohydride (1.0 g, 2.6 mmol) was addedin small portions and the reaction mixture was heated to 70° C. for 2 h.The cloudy solution was filtered and the solvent removed in vacuo.Toluene (150 ml) and water (80 ml) were added, the layers wereseparated, and the aqueous layer was extracted with toluene (50 ml). Thecombined toluene extracts were washed with water (50 ml), dried overMgSO₄ and evaporated in vacuo. The residue (9.03 g), which crystallisedafter standing was triturated with cyclohexane and filtered off, and thehereby obtained 12H-dibenzo-[d,g][1,3]dioxocin-12-ol was used in nextstep without further purification.

M.p. 80-90° C.

To a solution of the above alcohol (5.0 g, 22 mmol) in benzene (85 ml)triethylamine (5.5 g, 54 mmol) was added, and a solution ofmethanesulfonyl chloride (3.2 g, 28 mmol) in benzene (25 ml) was addeddropwise at 15-20° C. over 20 minutes under cooling on a cold waterbath. After addition, the reaction mixture was stirred for 2 h at roomtemperature. Water (35 ml) was added, and the organic layer wasseparated, washed with water (25 ml), dried over MgSO₄ and evaporated invacuo. To the residual oil (5.8 g), anhydrous potassium carbonate (8.6g, 62 mmol) and 2-bromoethanol (13.6 ml, 191 mmol) were added. Thereaction mixture was stirred for 17 h at room temperature, diluted withdichloromethane (60 ml), filtered and evaporated in vacuo. Solid12-(2-bromoethoxy)-12H-dibenzo[d,g][1,3]dioxocine (5.0 g, 68%) separatedfrom the residue after standing at room temperature and was filtered offand washed with petroleum ether.

M.p. 112-114° C.

A solution of the above bromide (1.7 g, 5 mmol),(R)-3-piperidinecarboxylic acid ethyl ester tartrate (2.1 g, 6.7 mmol)and potassium carbonate (1.1 g, 8 mmol) was stirred for 22 h at roomtemperature. Inorganic salts were filtered off, and the filtrate wasdiluted with water (130 ml) and extracted with diethyl ether (2×40 ml).The organic extracts were washed with water (2×20 ml), dried over MgSO₄and evaporated in vacuo. The oily residue, crude(R)-1-(2-(12H-dibenzo[d,g][1,3]-dioxocin-12-yloxy)-1-ethyl)-3-piperidinecarboxylicacid ethyl ester was used in the next step without further purification.

The above ester (1.6 g, 3.9 mmol) was dissolved in ethanol (16 ml) and20% sodium hydroxide (2.1 ml) was added. The reaction mixture wasstirred at room temperature for 18 h, poured into dichloromethane (320ml) and acidified with concentrated acetic acid (5.3 ml). The organicphase was washed with water (50 ml), dried over MgSO₄ and evaporated invacuo. The oily residue was re-evaporated twice with benzene thentriturated with acetone to give crystals of the title compound (0.96 g,55%).

M.p. 120-28° C.; Calculated for C₂₄ H₂₉ NO₇ : C, 65.00%; H, 6.59%; N,3.16%. Found: C, 65.21%; H, 6.70%; N, 3.06%.

EXAMPLE 9

(R)-1-(2-(2,10-Dichloro-12H-dibenzo[d,g][1,3]dioxocin-12-yloxy)-1-ethyl)-3-piperidinecarboxylicacid hydrochloride ##STR11##

Bis-(5-chloro-2-hydroxyphenyl)methane (25.0 g, 92.9 mmol) was dissolvedin N,N-dimethyl formamide (350 ml), and diiodomethane (7.8 ml, 97.5mmol) and potassium carbonate (18.6 g, 135 mmol) were added. The mixturewas heated to 105° C. overnight After cooling, the mixture was pouredinto icewater (1200 ml). A precipitate was formed immediately. Afterstirring for 30 minutes, the solid was filtered off and washed with asmall amount of water. The solid was suspended in a mixture (80:20) ofethanol and 4 M sodium hydroxide, and the resulting mixture was heatedat 80° C. for 1 h. After cooling, the mixture was poured into water (600ml), and the precipitate was filtered off. After drying, this afforded2,10-dichloro-12H-dibenzo[d,g][1,3]-dioxocine (24.8 g, 95%), which wasused for further reaction without purification.

The above dioxocine (7.7 g, 27 mmol) and N-bromosuccinimide (5.4 g, 30mmol) were suspended in tetrachloromethane (100 ml).Azobisisobutyronitrile (50 mg) was added and the mixture was heated atreflux temperature. During the first.7 h, every second hour, portions ofmore azobisisobutyronitrile (50 mg) were added. Heating was continuedovernight. Two additional portions of azobisisobutyronitie (50 mg) werethen added and heating at reflux temperature was continued for 24 h intotal. After cooling, the reaction mixture was filtered and evaporated.Dichloromethane (10 ml) and diethyl ether (15 ml) were added and thesolid was filtered off, affording after drying12-bromo-2,10-dichloro-12H-dibenzo[d,g][1,3]dioxocine (3.37g, 11%).

The above bromide (3.37 g, 9.36 mmol) was mixed with 2-bromoethanol (8.0ml, 110 mmol) and potassium carbonate (3.9 g, 28 mmol). The mixture wasstarred for 1 h at room temperature. Dichioromethane (10 ml) was addedto dilute the mixture, and stirring was continued overnight at roomtemperature. The mixture was heated at 120° C. for 24 h. After cooling,the mixture was evaporated, and ethyl acetate (100 ml) and water (100ml) were added. The phases were separated and the organic phase waswashed with water (100 ml). The combined aqueous phases were extractedwith ethyl acetate (100 ml). The organic extracts were dried (MgSO₄) andevaporated to give crude12-(2-bromoethoxy)-2,10-dichloro-12H-dibenzo[d,g][1,3]dioxocine (4.34g). The product was used for further reaction without purification.

The above bromoethoxy compound (4.25 g, 10.5 mmol) was suspended indimethyl sulfoxide (50 ml). (R)-3-Piperidinecarboxylic acid ethyl estertartrate (4.1 g, 13.7 mmol) and potassium carbonate (3.2 g, 23 mmol)were added. The reaction mixture was stirred at 50° C. overnight. Aftercooling and filtration, water (250 ml) was added and the mixture wasextracted with diethyl ether (2×100 ml). The organic extracts werewashed with water (75 ml), dried (MgSO₄) and evaporated. The residualoil was purified by column chromatography on silica gel (600 ml) using amixture of heptane and ethyl acetate (2:1) as eluent. This afforded(R)-1-(2-(2,10-dichloro-12H-dibenzo[d,g][1,3]dioxocin-12-yloxy)-1-ethyl)-3-piperidinecarboxylicacid ethyl ester (2.0 g, 40%) as an oil.

The above ester (0.78 g, 1.62 mmol), dissolved in a solution of sodiumhydroxide (0.54 g, 13.5 mmol) in ethanol (40 ml) and water (5 ml) wasstirred at room temperature for 3.5 h. The pH of the mixture wasadjusted to 4 by addition of 1 N hydrochloric acid (14 ml). The mixturewas extracted with dichloromethane (2×60 ml), the combined organicphases were washed with brine (75 ml), dried over MgSO₄ and the solventwas removed in vacuo. The residue was stirred with acetone (10 ml) for2.5 h, the solid product was filtered off and dried, affording the titlecompound (0.56 g, 71%).

M.p. 218-220° C.; Calculated for C₂₃ H₂₃ Cl₂ NO₅, HCl: C, 54.06%; H,4.95%; N, 2.87%; Found: C, 53.9%; H, 4.8%; N, 2.6%.

EXAMPLE 10

(R)-1-(3-(2-Chloro-12H-dibenzo[d,g,][1,3,6]dioxazocin-12-yl)-1-propyl)-3-piperidinecarboxylicacid hydrochloride ##STR12##

A suspension of 2-chloro-2H-dibenzo[d,g][1,3,6]dioxazocine (10.65 g, 43mmol, prepared as described in Journal of Molecular Structures, 131,1985, 131-140) and 3-chloropropionyl chloride (6.55 g, 51.6 mmol) in drytoluene (100 ml) was heated at reflux temperature for 5 h. After coolingto room temperature, the reaction mixture was washed with a saturatedsolution of sodium bicarbonate (50 ml). The organic layer was dried(MgSO₄), and evaporated in vacuo, which afforded2-chloro-12-(3-chloropropionyl)-12H-dibenzo[d,g][1,3,6]dioxazocine (12.9g, 88%).

A predried flask with lithium aluminium hydride (3.0 g, 79 mmol),suspended in dry tetrahydrofutran (80 ml), was cooled in an ice bath andconcentrated sulphuric acid (3.87 g, 39.5 mmol) was added dropwise at arate to maintain a temperature <12° C. The solution was stired at roomtemperature for 1.5 h. A solution of the above chloride (12.8 g, 37.8mmol) in dry tetraydrofuran (80 ml) was added dropwise and stirring wascontinued for 2 h. The reaction was quenched by careful addition ofethyl acetate (100 ml) followed by water (5.7 ml). Filtration of themixture and evaporation of the filtrate in vacuo afforded2-chloro-12-(3-chioropropyl)-12H-dibenzo[d,g][1,3,6]dioxazocine as afoam.

A mixture of the above crude chloride (1.14 g, 3.5 mmol),(R)-3-piperidinecarboxylic acid ethyl ester (L)-tartrate (1.05 g, 3.5mmol), dried potassium carbonate (1.94 g, 14 mmol), sodium iodide (0.53g, 3.5 mmol) and 2-butanone (15 ml) was heated at reflux temperature for60 h. The reaction mixture was filtered, the filtrate washed with2-butanone (10 ml) and the combined filtrates evaporated in vacuo. Thecrude product was purified by column chromatography on silica gel usinga mixture of ethyl acetate and heptane (1:3) containing triethylamine(2.5%) as eluent. This afforded the product,(R)-1-(3-(2-chloro-2H-dibenzo[d,g][1,3,6]dioxazocin-12-yl)-1-propyl)-3-piperidinecarboxylicacid ethyl ester (0.77 g, 49 ) as an oil.

The above ester (0.77 g, 1.73 mmol) was dissolved in ethanol (7.5 ml)and 2 N sodium hydroxide (2.86 ml, 5.71 mmol) was added. The mixture wasstirred at room temperature for 16 h. The ethanol was evaporated invacuo and the remainder was diluted with water (25 ml). pH was adjustedto 6 by addition of 6 N hydrochloric acid and the aqueous solution wasextracted with dichloromethane (3×15 ml). The combined organic extractswere dried over MgSO₄ and evaporated in vacuo. The remainder wasdissolved in tetrahydrofuran (15 ml) and 2.5 N hydrogen chloride inether (0.59 ml, 1.47 mmol) was added dropwise. Ether (30 ml) was addedand the mixture was stirred for 3 h, the precipitate was filtered offand dried, to afford 0.53 g (68%) of the title compound as a powder.

M.p. 177-180° C.; Calculated for C₂₂ H₂₅ ClN₂ O₄, HCl: C, 58.28%; H,5.78%; N, 6.18%; Found: C, 58.3%; H, 5.9%; N, 6.1%.

EXAMPLE 11

1-(3-(12H-Dibenzo[d,g][1,3,6]dioxazocin-12-yl)-1-propyl)-4-piperidinecarboxylicacid hydrochloride ##STR13##

N-(2-Hydroxyphenyl)formamide (16.0 g, 130 mnol) was dissolved in 99.9%ethanol (65 ml). Sodium methoxide 7.0 g, 130 mmol) was suspended in99.9% ethanol (70 mnl) and added dropwise over 30 minutes. The resultingmixture was stirred for 30 minutes. 1-Bromo-2-chloromethoxybenzene (26.1g, 118 mmol, synthesis described in J. Heterocycl. Chem., 11, 1974,331-337) was added dropwise over 15 minutes. The reaction mixture wasstirred for 2.5 h at room temperature, heated at reflux temperature for2 h, and stirred at room temperature overnight. The mixture was filteredand evaporated. The residue was dissolved in toluene (500 ml) and washedwith a saturated sodium carbonate solution (2×200 ml). The organic phasewas dried (MgSO₄) and evaporated. The residue was suspended in ethanol(40 ml), filtered and washed with ethanol (3×10 ml). After drying, thisafforded the product, N-(2-(2-bromophenoxymethoxy)phenyl)formamide (14.1g, 37%).

The above formamide (6.8 g, 21 mmol) was suspended in Dowtherm (75 ml),and potassium carbonate (3.9 g, 28 mmol) was added, followed by copper(1.1 g, 17 mmol) and copper bromide (1.5 g, 11 mmol). The reactionmixture was heated at 180° C. overnight. After cooling, the mixture wasfiltered, and the filter cake was washed with dichloromethane. Dowthermand solvent was distilled off, and ethanol (200 ml) was added to theresidue, which was left overnight. 4 M Sodium hydroxide (14 ml) wasadded, and the mixture was heated at reflux temperature for 1 h. Aftercooling, the mixture was filtered and evaporated. The residue wassuspended in ethyl acetate (200 ml) and water (100 ml). The organicphase was washed with water (2×75 ml). The aqueous phases were extractedwith ethyl acetate (100 ml). The combined organic extracts wereevaporated. The residue was suspended in warm cyclohexane (100 ml), andleft cooling under stirring. The precipitated solid was filtered off,affording after drying the product 12H-dibenzo[d,g][1,3,6]dioxazocine(4.57 g, 50%).

The above dioxazocine (4.0 g, 19 mmol) was dissolved in dryN,Ndirethylformamide (150 ml). Sodium hydride (1.13 g, 28 mmol, 60%dispersion in oil) was added in portions, and the resulting mixture wasstirred for 30 minutes at room temperature. 1-Bromo-3-chloropropane (4.6ml, 47 mmol) was slowly added dropwise, and the reaction mixture wasstirred at room temperature overnight. More sodium hydride (0.56 g, 14rnmol) was added, and stirring was continued for 6 h. More sodiumhydride (0.56 g, 14 mmol) was added, and stirring was continuedovernight. Ammonium chloride (3.2 g) was added, and the mixture wasstirred for 30 minutes. Water was added (300 ml), and the mixture wasextracted with dichloromethane (2×250 ml). The organic extracts weredried (MgSO₄) and evaporated. The residue was purified by columnchromatography on silica gel using a mixture of heptane and ethylacetate (6:1) as eluent. This afforded the product,12-(3-chloropropyl)-12H-dibenzo[d,g][1,3,6]dioxazocine (2.18 g, 40%).

The above chloride (1.0 g, 3.5 mmol) and potassium iodide (3.7 g, 22mmol) in methyl ethyl ketone (110 ml) was heated at reflux temperaturefor 4 h. 4-Piperidinecarboxylic acid ethyl ester (0.8 g, 5.2 mmol) wasdissolved in methyl ethyl ketone (5 ml) and added, followed by potassiumcarbonate (1.2 g, 8.6 mmol). The reaction mixture was heated at refluxtemperature for 48 h. After cooling, the mixture was filtered, thefilter cake was washed with methyl ethyl ketone, and the filtrate wasevaporated. The residual oil was purified by column chromatography onsilica gel (500 ml) using ethyl acetate as eluent. This afforded1-(3-(12H-dibenzo[d,c][1,3,6]dioxazocin-12-yl)-1-propyl)-4piperidinecarboxylicacid ethyl ester (0.80 g, 57%) as an oil.

The above ester (0.50 g, 1.22 mmol), dissolved in a solution of sodiumhydroxide (0.24 g, 6 mmol) in ethanol (30 ml) and water (3 ml) wasstirred at room temperature for 3 h. The pH of the mixture was adjustedto 3 by addition of 1 N hydrochloric acid (5 ml). The mixture wasextracted with dichloromethane (2×40 ml), the combined organic phaseswere washed with brine (50 ml), dried over MgSO₄ and the solvent wasremoved in vacuo. The residue was triturated with acetone (20 ml), thesolid product was filtered off and dried, affording the title compoundin quantitative yield (0.52 g).

M.p. 180-187° C.; Calculated for C₂₂ H₂₆ N₂ O₄, HCl, 1.25 H₂ O: C,59.85%; H, 6.74%; N, 6.35%; Found: C, 59.85%; H, 6.60%; N, 6.00%.

What is claimed is:
 1. A compound of formula I ##STR14## wherein R¹ andR² independently are hydrogen, halogen, trifluoromethyl, hydroxy, C₁₋₆-alkyl or C₁₋₆ -alkoxy; andR³ is hydrogen or C₁₋₃ -alkyl; and A is C₁₋₃-alkylene; and Y is CH--CH2--, C═CH--, CH--O-- or C═N--, CH--CH₂ --,C═CH--, CH--O-- or C═N--, wherein only the underscored atom participatesin the ring system; and Z is ##STR15## wherein n is 1 or 2; R¹¹ ishydrogen or C₁₋₆ -alkyl; R¹⁴ is --(CH₂)_(m) OH or --(CH₂)_(t) COR¹⁵wherein m is 0, 1, 2, 3, 4, 5 or 6, t is 0 or 1, and R¹⁵ is --OH, NH₂,--NHOH or C₁₋₆ -alkoxy; or a pharmaceutically acceptable salt thereof.2. A compound of claim 1, wherein R¹ and R² independently are hydrogenor halogen.
 3. A compound of claim 1, wherein R¹⁴ is --(CH₂)_(t) COR¹⁵wherein t is 0 or 1 and wherein R¹⁵ is --OH.
 4. A pharmaceuticalcomposition comprising as an active component a therapeuticallyeffective amount of a compound of claim 1 together with apharmaceutically acceptable carrier or diluent.
 5. The pharmaceuticalcomposition of claim 4, comprising between 0.5 mg and 1000 mg of thecompound.